In the pharmaceutical industry the most commonly employed means to deliver active pharmaceutical ingredients (hereinafter “API” or “APIs”) is the tablet, which may be obtained through the compression of appropriately formulated powders. Conventional, compressible mixtures are typically obtained by the blending of an API and suitable excipient materials. These excipients may include diluents or fillers/carriers, binders or adhesives, disintegrants, glidants or flow promoters, colours, flavours and mixtures thereof. A glidant is a substance that is added to a powder to improve its flowability into the tableting device.
As mentioned in WO2008/020990 these materials may simply be blended, or may be granulated in either the dry or wet state. Once mixing is complete, a lubricating excipient is added and the material compressed into tablets. WO2008/020990 itself is striving for a universal excipient blend that maximizes the ability of APIs to be formulated without adversely affecting its safety and efficacy profiles. The blend would be mixed with an API and optionally a lubricant, then compressed into tablets. This is also confirmed in U.S. Pat. No. 3,344,030. The flow charts at page 14, 15 and 17-19 of WO 2007/031933 perfectly demonstrate that a lubricant should be added after granulation and milling of the granule, only to be followed by compaction. WO01/41744, at page 31 in particular, teaches to prepare pellets by coating spheroids containing an API and pre-mixed excipient components with a suspension containing magnesium stearate. Independent on the way of tableting, a lubricant is blended with carrier and active compound only just prior to compression.
Likewise, U.S. Pat. No. 5,006,345 provides a direct tableting auxiliary based on lactose powder mixed intimately with a binder, and a tablet disintegrant agent. After mixing these with the API, a lubricant is only then added and the mixture is pressed to produce tablets. WO 97/44014, US 2006/0246135, WO 2007/086689, U.S. Pat. No. 6,514,524 and WO 02/03963 teach similarly. In all events, a lubricant is again added immediately preceding compaction, after pre-mixing of the other excipient components.
Outside the field of providing ready-to-use co-processed tablet excipient components, WO 2004/110406 and US 2006/0247234 both disclose processes in which the API, excipients and lubricant are mixed altogether.
In the field, however, a lubricant is deemed necessary to realise release of the compressed form or tablet from the device. However, at the same time it is believed that the lubricant could affect the necessary binding between the various carrier components and, in the case of hydrophobic lubricants such as magnesium stearate, tablet disintegration properties negatively. Regarding the binding properties, the reasons would rest in the tendency of lubricants to coat the excipient components, thus preventing these from adhering to one another. Also, a hydrophobic lubricant coat repels water which plays an important role in disintegration. Therefore, the use of lubricant is postponed until mixing of all components has been achieved, so as to minimize contact time between lubricant and other tablet components prior to the actual compression step.
In the art, WO 2009/112287 recently disclosed that the lubricant can already be added to the co-processing step, thus providing a ready-to-use excipient composition which would conveniently require only the steps of adding the API(s) and compression, and still expedite ejection from the tableting die. Despite the use of lubricant at an earlier processing stage, the die ejection force and tablet force are excellent. However, to yield these properties, the process of WO 2009/112287 involves spraying of the lubricant onto the cogranulated components, thus creating a lubricant coat covering the granules. It thus continues to feed the skilled person's belief that the lubricant should make direct contact with the die, which can only be achieved when spraying it as an outside layer to the excipient composition.
In the art, there is however the continuous need for further optimizing the process for producing ready-to-use co-processed excipient compositions.